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Benchmarking of gastric cancer sensitivity to anti-cancer drugs ex vivo as a basis for drug selection in systemic and intraperitoneal therapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
Västmanlands sjukhus, Kirurgkliniken, Västerås, Sverige.
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2014 (English)In: Journal of Experimental & Clinical Cancer Research, ISSN 1756-9966, E-ISSN 1756-9966, Vol. 33, 110Article in journal (Refereed) Published
Abstract [en]

Background  

The choice of drugs for treatment of advanced gastric cancer (GC) is empirical. The purpose of the current study was to benchmark ex vivo the sensitivity of GC tumor cells from patients to standard cytotoxic and some newly introduced targeted drugs (TDs), as a basis for drug selection in the treatment of GC.

Methods  

Tumor cell samples from patients with GC were analyzed for sensitivity to 5-fluorouracil, cisplatin, oxaliplatin, irinotecan, mito­mycin C, doxorubicin and docetaxel as well as for the targeted drugs bortezomib, sorafenib, sunitinib and rapamycin using a short-term in vitro assay based on retention of viable tumor cells of fluorescent fluorescein. Samples of normal mononuclear cells, chronic lymphocytic leukemia, ovarian cancer and colorectal cancer were included for comparison.

Results    

The GC samples were essentially as sensitive to the standard drugs and the TDs as those from colorectal cancer whereas the ovarian cancer samples were more sensitive. The individual GC samples varied considerably in sensitivity to increasing concentrations of the clinically used standard drugs. In GC, cisplatin was cross-resistant to oxaliplatin and 5-fluorouracil which, on the other hand, was not cross-resistant to the other cytotoxic drugs. The activity of sunitinib did not obviously correlate to that of the standard drugs.

Conclusion    

Ex vivo assessment of drug sensitivity of tumor cells from patients with GC is feasible and may provide information that could be useful for selection of drugs for treatment. Drug sensitivity varies considerably between and within individual samples arguing for individualized selection of drugs for chemotherapy.

Place, publisher, year, edition, pages
2014. Vol. 33, 110
Keyword [en]
gastric cancer, cultured tumor cells, fluorometric analysis, cancer drug tests, chemo-sensitivity, anti tumor drugs
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-197739DOI: 10.1186/s13046-014-0110-9ISI: 000349128000002PubMedID: 25528067OAI: oai:DiVA.org:uu-197739DiVA: diva2:614041
Note

Submitted article title: Benchmarking of gastric cancer tumor cell sensitivity ex vivo to standard and targeted anti-cancer drugs as a basis for drug selection in systemic and intraperitoneal therapy

Available from: 2013-04-03 Created: 2013-04-03 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Clinical and Experimental Studies in Peritoneal Metastases from Gastric Cancer
Open this publication in new window or tab >>Clinical and Experimental Studies in Peritoneal Metastases from Gastric Cancer
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gastric cancer (GC) is one of leading causes of death in the world, and peritoneal metastases (PM) are a major site of recurrence. PM from GC implies a poor prognosis, with median overall survival (mOS) approximately 3 months and no survival at five years.

The aims of this thesis were to explore the incidence and evaluate prognostic factors for mOS of PM from GC in a defined population; to investigate the outcome of a new multimodal treatment; to analyse the treatment costs, and to investigate differences in drug sensitivity between individual patient samples and between various tumours.

The incidence of loco-regional advanced GC was 3.8 per 100,000 person-years. Synchronous loco-regional GC in combination with synchronous distant metastasis was a negative prognostic factor while chemotherapy and good performance status, and radiotherapy plus chemotherapy were positive prognostic factors . There were no significant differences in mOS for the group of patients included during the period 2000-2004 versus 2005-2009, and this lack of improvement in mOS during the past decade justifies new treatment approaches.

In a Phase II study of patients treated with neoadjuvant systemic chemotherapy followed by cytoreductive surgery + hyperthermic intraperitoneal chemotherapy, mOS was 14.3 months and for patients with macroscopically radical surgery mOS was 19.1 months. The mean overall cost of the loco-regional treatment was $145,700 compared to $59,300 with systemic chemotherapy treatment.

In an ex vivo chemo-sensitivity test, it was determined that GC samples were equivalent to colorectal cancer in chemo-sensitivity to standard drugs and targeted drugs, whereas ovarian cancer samples were more sensitive. The individual GC samples varied considerably in sensitivity to increasing concentrations of the drugs, arguing for individualized drug selection. The incidence of loco-regional advanced GC was more common than previously reported and there were no improvements in mOS over the past decade. The mOS for patients with neoadjuvant systemic chemotherapy followed by macroscopically radical cytoreductive surgery + hyperthermic intraperitoneal chemotherapy was better than in recent reports on treatment with systemic chemotherapy. Treatment of advanced GC patients is costly irrespective of treatment modality. The GC samples varied considerably between individuals in terms of sensitivity to increasing concentrations of the drugs and were comparable to colorectal cancer in chemo-sensitivity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 886
Keyword
gastric cancer, peritoneal metastases, peritoneal carcinomatosis, epidemiology, prognostic factor, survival, neoadjuvant chemotherapy, cytoreductive surgery, HIPEC, health economy, costs, systemic chemotherapy, cultured tumor cells, fluorometric analysis, cancer drug tests, chemo-sensitivity, anti tumor drugs.
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:uu:diva-197776 (URN)978-91-554-8635-8 (ISBN)
Public defence
2013-05-18, Gustavianum, Auditorium minus, Akademigatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2013-04-26 Created: 2013-04-03 Last updated: 2013-08-30Bibliographically approved

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Hultman, BoMahteme, HaileSundbom, MagnusLarsson, RolfNygren, Peter

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